WO2019089335A1 - Agonistes de triazole fusionnés du récepteur apj - Google Patents

Agonistes de triazole fusionnés du récepteur apj Download PDF

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Publication number
WO2019089335A1
WO2019089335A1 PCT/US2018/057466 US2018057466W WO2019089335A1 WO 2019089335 A1 WO2019089335 A1 WO 2019089335A1 US 2018057466 W US2018057466 W US 2018057466W WO 2019089335 A1 WO2019089335 A1 WO 2019089335A1
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alkyl
pharmaceutically acceptable
acceptable salt
tautomer
compound
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PCT/US2018/057466
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English (en)
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Paul John Dransfield
James S. HARVEY
Zhihua Ma
Ankit Sharma
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Amgen Inc.
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Priority to EP18804753.4A priority Critical patent/EP3704122B1/fr
Priority to US16/760,947 priority patent/US11149040B2/en
Publication of WO2019089335A1 publication Critical patent/WO2019089335A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to compounds capable of acting as agonists of the APJ Receptor, and compositions that include compounds that are agonists of the APJ Receptor.
  • the compounds and compositions may be used to activate the APJ Receptor and to treat various disease conditions.
  • An example of one area where such compounds may be used is in the treatment of cardiovascular conditions.
  • the compounds may be used to improve contractility and ejection fraction in subjects with chronic heart failure and may be used to treat patients with heart failure with reduced ejection fraction and patients with heart failure with preserved ejection fraction.
  • Apelin is the endogenous ligand for APJ (APLNR, angiotensin receptor like-1).
  • APLNR angiotensin receptor like-1
  • the APJ receptor is a member of the rhodopsin-like G protein-coupled receptor (GPCR) family.
  • GPCR G protein-coupled receptor
  • the apelin/APJ system has been observed in many tissues such as heart, kidney, pancreas, lung and the central nervous system. This suggests diverse roles of the system in the physiology and pathology of mammals.
  • Apelin peptides are processed from a 77 residue pre-pro form into smaller bioactive fragments, mainly a 36 residue form (Apelin 42-77- also referred to as Apelin-36) and a smaller 13 residue polypeptide (Apelin 65-77-also referred to as Apelin- 13) Hosoya et al., J. Biol. Chem. 275:21061-21067, 2000.
  • Apelin peptides were previously determined to be endogenous ligands for the orphan APJ receptor, a member of the seven transmembrane G-protein-coupled receptor superfamily. Tatemoto et al., Biochem. Biophysi. Res. Commun.
  • exogenous apelin increases contractility at subnanomolar concentrations in atrial strips and whole rat hearts, and increases sarcomere shortening by up to 140% in isolated cardiomyocyctes.
  • Apelin also has a potent inotropic effect in an ex vivo isolated heart assay.
  • acute apelin infusion restores ejection fraction, increases cardiac output and reduces left ventricular end-diastolic pressure in rats with chronic heart failure.
  • Exogenous apelin potently enhances myocardial contractility without inducing left ventricular hypertrophy concomitant with reduction in ventricular preload and afterload.
  • a shortened 12 amino acid-apelin peptide having ligand activity on APJ was reported in a 2009 patent (U.S. Pat. No. 7,635,751).
  • the peptide could have a substitution of one non-canonical amino acid.
  • WO 2013/111110 A2 and U.S. Pat. No. 8,673,848, cyclic mimetics of apelin have also been reported.
  • Another study reported synthesizing analogs of apelin-13 with amino acid substitutions with non-canonical amino acids at the C-terminal end of the molecule, but no pegylation at the N- or C-terminus or another site specific location.
  • PCT/US2013/075773 describes a group of modifications, including substitution of non-canonical amino acids and changes at the N- and C-terminal of the apelin molecule that can affect, inter alia, the potency of the molecule.
  • the increased potency can be a result of increased half-life or decreased degradation relative to wild- type apelin.
  • WO 2014/044738 discloses various benzimidazole- carboxylic acid amide derivatives as modulators of the APJ Receptor.
  • Other small molecule agonists of the APJ receptor are disclosed in U.S. Pat. Appl. Pub. No. US 2016/0340336 and WO 2016/187308.
  • Still other small molecule agonists of the APJ receptor are disclosed in WO 2015/184011 and in WO 2015/188073.
  • the present application discloses such agonists of the APJ receptor s that may be suitable for use as therapeutic agents in treating a variety of conditions. These compounds may find particular benefit in treating cardiovascular conditions. For example, such compounds may be beneficial in treating conditions such as chronic systolic heart failure and chronic diastolic heart failure.
  • the invention provides a compound of Formula I:
  • R 1 and R 4 together with the C and N atoms of the triazole to which they are attached join to form a B ring, wherein the B ring is a 5 to 10 membered saturated or partially unsaturated ring that includes 0, 1, 2, or 3 heteroatoms independently selected from N, O, and S in addition to the N atom of the triazole that bears the R 4 substituent, wherein the B ring is substituted with 0, 1, 2, or 3 R B substituents; and further wherein the 5 to 10 membered B ring is fused to a C ring, wherein the C ring is selected from a phenyl ring, a 5 or 6 membered heteroaryl ring that includes 1, 2, or 3 heteroatoms independently selected from N, O, or S, a 5 to 7 membered heterocyclyl ring that includes 1, 2, or 3 heteroatoms independently selected from N, O, or S, or a C4 to Cg cycloalkyl ring, wherein the C ring is substituted with 0, 1, 2,
  • R B is independently selected from -F, -CI, -Br, -I, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -Ci-Cg perhaloalkyl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -CN, -OH, -0-(Ci-C 6 alkyl), -0-(Ci- C 6 haloalkyl), -0-(Ci-C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -0-(Ci-C 6 alkyl)-OH, -0-(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -0-(Ci-C 6 haloalkyl) -OH, -0-(Ci-C 6 haloalkyl)-0-(Ci-C 6 alkyl), - 0-(Ci-C 6 perhalo
  • R c is independently selected from -F, -CI, -Br, -I, -Ci-Ce alkyl, -Ci-Ce haloalkyl, - Ci-Ce perhaloalkyl, -(Ci-Ce alkyl)-0-(Ci-C 6 alkyl), -CN, -OH, -0-(Ci-C 6 alkyl), -0-(Ci- C 6 haloalkyl), -0-(Ci-C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -0-(Ci-C 6 alkyl)-OH, -0-(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -0-(Ci-C 6 haloalkyl) -OH, -0-(Ci-C 6 haloalkyl)-0-(Ci-C 6 alkyl), - 0-(Ci-C 6 perhalo
  • R 2 is selected from -H, or C1-C4 alkyl
  • R 3 is selected from a group of formula -(CR 3b R 3c )-Q, a group of formula -(CR 3d R 3e )-(CR 3f R 3g )-Q, or a group of formula -(heterocyclyl)-Q, wherein the heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R 3h substituents;
  • R 3b and R 3c are independently selected from -H, -F, -CI, -CN, -Ci-C 6 alkyl, -Ci- C 6 haloalkyl, -Ci-C 6 perhaloalkyl, -OH, -0-(Ci-C 6 alkyl), -0-(Ci-C 6 haloalkyl), -0-(Ci-C 6 perhaloalkyl), -0-(Ci-C 6 alkyl)-OH, -0-(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), or -N(Ci-C 6 alkyl) 2 ;
  • R 3d and R 3e are independently selected from -H, -F, -CI, -CN, -Ci-C 6 alkyl, -Ci- C 6 haloalkyl, -Ci-C 6 perhaloalkyl, -OH, -(Ci-C 6 alkyl)-OH, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -(Ci-Ce alkyl)-0-(Ci-C 6 alkyl)-phenyl, -0-(Ci-C 6 alkyl), -0-(Ci-C 6 haloalkyl), -O- (Ci-Cg perhaloalkyl), -0-(Ci-C 6 alkyl)-OH, -0-(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -NH 2 , - NH(Ci-C 6 alkyl), or -N(Ci-C
  • R 3f and R 3g are independently selected from -H, -F, -CI, -CN, -Ci-C 6 alkyl, -Ci- C 6 haloalkyl, -Ci-C 6 perhaloalkyl, -OH, -(Ci-C 6 alkyl)-OH, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -0-(Ci-C 6 alkyl), -0-(Ci-C 6 haloalkyl), -0-(Ci-C 6 perhaloalkyl), -0-(C 2 -C 6 alkenyl), -0-(Ci-C 6 alkyl)-OH, -0-(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), or -N(Ci-C 6 alkyl) 2 ;
  • Q is a monocyclic or bicyclic Ce-Cw aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C3-C8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the Ce-Cw aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R Q substituents; and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom; and
  • alkyl alkyl
  • alkyl alkyl
  • the compound of Formula I has the Formula IIA,
  • compositions that include at least one pharmaceutically acceptable excipient, carrier or diluent and the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof according to any one of the embodiments.
  • the invention provides a method of treating a cardiovascular condition.
  • Such methods typically include administering to a subject an effective amount of the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments.
  • the cardiovascular condition is heart failure.
  • the cardiovascular condition is heart failure with reduced ejection fraction whereas in other embodiments it is heart failure with preserved ejection fraction.
  • the cardiovascular condition is chronic systolic heart failure or chronic diastolic heart failure.
  • the cardiovascular condition is acute heart failure whereas in other embodiments, the cardiovascular condition is hypertension.
  • the invention provides a method of improving cardiac contractility in a subject.
  • Such methods typically include administering to the subject an effective amount of the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments.
  • the invention provides a method of increasing ejection fraction in a subject suffering from a cardiovascular condition.
  • Such methods typically include administering to the subject an effective amount of the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments.
  • the ejection fraction is increased in the subject after administration.
  • the invention provides a method of treating a condition in a subject where it is desired to activate the APJ Receptor.
  • Such methods typically include administering to the subject an effective amount of the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments.
  • the condition is obesity or diabetes whereas in other such embodiments, the condition is diabetic nephropathy or chronic kidney disease.
  • the invention provides the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, tor the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments for use in treating a cardiovascular condition.
  • the cardiovascular condition is heart failure.
  • the cardiovascular condition is heart failure with reduced ejection fraction whereas in other embodiments it is heart failure with preserved ejection fraction.
  • the cardiovascular condition is chronic systolic heart failure or chronic diastolic heart failure.
  • the cardiovascular condition is acute heart failure whereas in other embodiments, the cardiovascular condition is hypertension.
  • the invention provides the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments for improving the cardiac contractility in a subject suffering from a cardiovascular condition.
  • the invention provides the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments for improving the ejection fraction in a subject suffering from a cardiovascular condition.
  • the invention provides the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof according to any one of the embodiments or a pharmaceutical composition of any of the embodiments for treating a condition in a subject where it is desired to activate the APJ Receptor.
  • the condition is obesity or diabetes whereas in other such embodiments, the condition is diabetic nephropathy or chronic kidney disease.
  • FIG. 1 is a graph plotting different concentrations of angiotensin (Angll) with fixed concentration of pyr apelin-13 added to the human APJ-AT1R (angiotensin Type 1) double stable CHO cell line.
  • IP1 inositol phosphate accumulation
  • TR-FRET Time-resolved fluorescence resonance energy
  • FIG. 2 is a graph plotting different concentrations of angiotensin (Angll) with fixed concentration of pyr apelin-13 added to the human APJ receptor expressed in the CHO cell line.
  • IP1 inositol phosphate accumulation
  • TR-FRET Time-resolved fluorescence resonance energy
  • IP1 inositol phosphate accumulation
  • TR-FRET Time-resolved fluorescence resonance energy
  • any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. If the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound.
  • the compounds of the present disclosure may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers.
  • any chemical structures within the scope of the specification depicted, in whole or in part, with a relative configuration encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
  • Enantiomeric and stereoisomeric mixtures can be resolved into the component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.
  • composition is meant to be open ended, i.e., all encompassing and non-limiting. It may be used herein synonymously with “having” or “including”. Comprising is intended to include each and every indicated or recited component or element(s) while not excluding any other components or elements. For example, if a composition is said to comprise A and B. This means that the composition has A and B in it, but may also include C or even C, D, E, and other additional components.
  • Certain compounds of the invention may possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the invention.
  • atropisomers and mixtures thereof such as those resulting from restricted rotation about two aromatic or heteroaromatic rings bonded to one another are intended to be encompassed within the scope of the invention.
  • the barrier of rotation is high enough that the different atropisomers may be separated and isolated.
  • stereomerically pure means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound.
  • a stereomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound.
  • a stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
  • stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.
  • a bond drawn with a wavy line indicates that both stereoisomers are encompassed. This is not to be confused with a wavy line drawn perpendicular to a bond which indicates the point of attachment of a group to the rest of the molecule.
  • mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention.
  • These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al. (1997) Tetrahedron 33:2725; Eliel, E.
  • tautomers associated with compounds of the invention are those with a pyridone group (a pyridinyl) for which hydroxy pyridine is a tautomer and compounds with a ketone group with the enol tautomer. Examples of these are shown below.
  • Compounds of the present disclosure include, but are not limited to, compounds of Formula I and all pharmaceutically acceptable forms thereof.
  • the compounds described herein are in the form of pharmaceutically acceptable salts.
  • the term "compound” encompasses not only the compound itself, but also a pharmaceutically acceptable salt thereof, a solvate thereof, a chelate thereof, a non-covalent complex thereof, a prodrug thereof, and mixtures of any of the foregoing.
  • the term “compound” encompasses the compound itself, pharmaceutically acceptable salts thereof, tautomers of the compound, pharmaceutically acceptable salts of the tautomers, and ester prodrugs such as (Ci- C ⁇ alkyl esters. In other embodiments, the term “compound” encompasses the compound itself, pharmaceutically acceptable salts thereof, tautomers of the compound, pharmaceutically acceptable salts of the tautomers.
  • solvate refers to the compound formed by the interaction of a solvent and a compound. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates.
  • the compounds of the invention may also contain naturally occurring or unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention. For example, if a variable is said or shown to be H, this means that variable may also be deuterium (D) or tritium (T).
  • Alkyl refers to a saturated branched or straight-chain monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
  • Typical alkyl groups include, but are not limited to, methyl, ethyl, propyls such as propan-l-yl and propan-2-yl, butyls such as butan-l-yl, butan-2-yl, 2-methyl-propan-l-yl, 2-methyl-propan-2-yl, tert-butyl, and the like.
  • an alkyl group comprises 1 to 20 carbon atoms.
  • alkyl groups include 1 to 10 carbon atoms or 1 to 6 carbon atoms whereas in other embodiments, alkyl groups include 1 to 4 carbon atoms. In still other embodiments, an alkyl group includes 1 or 2 carbon atoms. Branched chain alkyl groups include at least 3 carbon atoms and typically include 3 to 7, or in some embodiments, 3 to 6 carbon atoms. An alkyl group having 1 to 6 carbon atoms may be referred to as a (Ci-C6)alkyl group and an alkyl group having 1 to 4 carbon atoms may be referred to as a (Ci-C4)alkyl. This nomenclature may also be used for alkyl groups with differing numbers of carbon atoms.
  • alkyl may also be used when an alkyl group is a substituent that is further substituted in which case a bond between a second hydrogen atom and a C atom of the alkyl substituent is replaced with a bond to another atom such as, but not limited to, a halogen, or an O, N, or S atom.
  • a group -0-(Ci-Ce alkyl)-OH will be recognized as a group where an -O atom is bonded to a Ci-Ce alkyl group and one of the H atoms bonded to a C atom of the Ci-Ce alkyl group is replaced with a bond to the O atom of an -OH group.
  • a group -0-(Ci-Ce alkyl)-0-(Ci-Ce alkyl) will be recognized as a group where an -O atom is bonded to a first Ci-Ce alkyl group and one of the H atoms bonded to a C atom of the first Ci-Ce alkyl group is replaced with a bond to a second O atom that is bonded to a second Ci-Ce alkyl group.
  • Alkenyl refers to an unsaturated branched or straight-chain hydrocarbon group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
  • the group may be in either the Z- or E- form (cis or trans) about the double bond(s).
  • Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-l-en-l-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), and prop-2-en-2-yl; butenyls such as but-l-en-l-yl, but-l-en-2-yl, 2-methyl-prop-l-en-l-yl, but-2-en-l-yl, but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, and buta-l,3-dien-2-yl; and the like.
  • an alkenyl group has 2 to 20 carbon atoms and in other embodiments, has 2 to 6 carbon atoms.
  • An alkenyl group having 2 to 6 carbon atoms may be referred to as a (C2-C6)alkenyl group.
  • Alkynyl refers to an unsaturated branched or straight-chain hydrocarbon having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyl; butynyl, 2-pentynyl, 3-pentynyl, 2- hexynyl, 3-hexynyl and the like.
  • an alkynyl group has 2 to 20 carbon atoms and in other embodiments, has 2 to 6 carbon atoms.
  • An alkynyl group having 2 to 6 carbon atoms may be referred to as a -(C 2 -C6)alkynyl group.
  • Alkoxy refers to a radical -OR where R represents an alkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. Typical alkoxy groups include 1 to 10 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms in the R group. Alkoxy groups that include 1 to 6 carbon atoms may be designated as -0-(Ci-Ce) alkyl or as -0-(Ci-Ce alkyl) groups. In some embodiments, an alkoxy group may include 1 to 4 carbon atoms and may be designated as -0-(Ci-C4) alkyl or as -0-(Ci-C4 alkyl) groups.
  • Aryl refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Aryl encompasses monocyclic carbocyclic aromatic rings, for example, benzene.
  • Aryl also encompasses bicyclic carbocyclic aromatic ring systems where each of the rings is aromatic, for example, naphthalene.
  • Aryl groups may thus include fused ring systems where each ring is a carbocyclic aromatic ring.
  • an aryl group includes 6 to 10 carbon atoms. Such groups may be referred to as Ce-Cw aryl groups.
  • Aryl does not encompass or overlap in any way with heteroaryl as separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with an aromatic ring that includes at least one heteroatom, the resulting ring system is a heteroaryl group, not an aryl group, as defined herein.
  • Cycloalkyl refers to a saturated cyclic alkyl group derived by the removal of one hydrogen atom from a single carbon atom of a parent cycloalkane.
  • Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, and the like. Cycloalkyl groups may be described by the number of carbon atoms in the ring.
  • a cycloalkyl group having 3 to 8 ring members may be referred to as a (C 3 -Cg)cycloalkyl
  • a cycloalkyl group having 3 to 7 ring members may be referred to as a (C 3 -Cv)cycloalkyl
  • a cycloalkyl group having 4 to 7 ring members may be referred to as a (C 4 -Cv)cycloalkyl.
  • the cycloalkyl group can be a
  • (C 3 -Cio)cycloalkyl a (C 3 -Cg)cycloalkyl, a (C 3 -Cv)cycloalkyl, a (C 3 -C6)cycloalkyl, or a (C4-Cv)cycloalkyl group and these may be referred to as C3-C10 cycloalkyl, C3-C8 cycloalkyl, C3-C7 cycloalkyl, C3-C6 cycloalkyl, or C4-C7 cycloalkyl groups using alternative language.
  • Heterocyclyl and “heterocyclic” refer to a cyclic group that includes at least one saturated, partially unsaturated, but non-aromatic, cyclic ring.
  • Heterocyclyl groups include at least one heteroatom as a ring member. Typical heteroatoms include, O, S and N and are independently chosen.
  • Heterocyclyl groups include monocyclic ring systems and bicyclic ring systems.
  • Bicyclic heterocyclyl groups include at least one non- aromatic ring with at least one heteroatom ring member that may be fused to a cycloalkyl ring or may be fused to an aromatic ring where the aromatic ring may be carbocyclic or may include one or more heteroatoms.
  • the point of attachment of a bicyclic heterocyclyl group may be at the non-aromatic cyclic ring that includes at least one heteroatom or at another ring of the heterocyclyl group.
  • a heterocyclyl group derived by removal of a hydrogen atom from one of the 9 membered heterocyclic compounds shown below may be attached to the rest of the molecule at the 5 -membered ring or at the 6- membered ring.
  • a heterocyclyl group includes 5 to 10 ring members of which 1, 2, 3 or 4 or 1, 2, or 3 are heteroatoms independently selected from O, S, or N. In other embodiments, a heterocyclyl group includes 3 to 7 ring members of which 1, 2, or 3 heteroatom are independently selected from O, S, or N. In such 3-7 membered heterocyclyl groups, only 1 of the ring atoms is a heteroatom when the ring includes only 3 members and includes 1 or 2 heteroatoms when the ring includes 4 members. In some embodiments, a heterocyclyl group includes 3 or 4 ring members of which 1 is a heteroatom selected from O, S, or N.
  • a heterocyclyl group includes 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from O, S, or N.
  • Typical heterocyclyl groups include, but are not limited to, groups derived from epoxides, aziridine, azetidine, imidazolidine, morpholine, piperazine, piperidine, hexahydropyrimidine, 1,4,5,6-tetrahydropyrimidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran, benzimidazolone, pyridinone, and the like.
  • Heterocyclyl groups may be fully saturated, but may also include one or more double bonds.
  • heterocyclyl groups include, but are not limited to, 1,2,3, 6-tetrahydropyridinyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, 2,5- dihydro-lH-pyrolyl, 2,3-dihydro-lH-pyrolyl, lH-azirinyl, 1,2-dihydroazetenyl, and the like.
  • Substituted heterocyclyl also includes ring systems substituted with one or more oxo
  • a saturated 5-membered hetereocycle containing one heteroatom which is a S may include the following heterocy
  • Disease refers to any disease, disorder, condition, symptom, or indication.
  • Halo or halogen refers to a fluoro, chloro, bromo, or iodo group.
  • Haloalkyl refers to an alkyl group in which at least one hydrogen is replaced with a halogen.
  • haloalkyl includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with two or more halogen atoms).
  • Representative “haloalkyl” groups include difluoromethyl, 2,2,2- trifluoroethyl, 2,2,2-trichloroethyl, and the like.
  • perhaloalkyl means, unless otherwise stated, an alkyl group in which each of the hydrogen atoms is replaced with a halogen atom.
  • perhaloalkyl includes, but is not limited to, trifluoromethyl, pentachloroethyl, l,l,l-trifluoro-2-bromo-2-chloroethyl, and the like.
  • Heteroaryl refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system. Heteroaryl groups typically include 5- to 14-membered, but more typically include 5- to 10-membered aromatic, monocyclic, bicyclic, and tricyclic rings containing one or more, for example, 1, 2, 3, or 4, or in certain embodiments, 1, 2, or 3, heteroatoms chosen from O, S, or N, with the remaining ring atoms being carbon. In monocyclic heteroaryl groups, the single ring is aromatic and includes at least one heteroatom.
  • a monocyclic heteroaryl group may include 5 or 6 ring members and may include 1, 2, 3, or 4 heteroatoms, 1, 2, or 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom where the heteroatom(s) are independently selected from O, S, or N.
  • bicyclic aromatic rings both rings are aromatic.
  • bicyclic heteroaryl groups at least one of the rings must include a heteroatom, but it is not necessary that both rings include a heteroatom although it is permitted for them to do so.
  • heteroaryl includes a 5- to 7- membered heteroaromatic ring fused to a carbocyclic aromatic ring or fused to another heteroaromatic ring.
  • the rings are aromatic and at least one of the rings includes at least one heteroatom.
  • the point of attachment may be at the ring including at least one heteroatom or at a carbocyclic ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another.
  • the total number of S and O atoms in the heteroaryl group is not more than 2.
  • the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • Heteroaryl does not encompass or overlap with aryl as defined above.
  • heteroaryl groups include, but are not limited to, groups derived from acridine, carbazole, cinnoline, furan, imidazole, indazole, indole, indolizine, isobenzofuran, isochromene, isoindole, isoquinoline, isothiazole, 2H-benzo[d][l,2,3]triazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, tri
  • the heteroaryl group can be between 5 to 20 membered heteroaryl, such as, for example, a 5 to 14 membered or 5 to 10 membered heteroaryl.
  • heteroaryl groups can be those derived from thiophene, pyrrole, benzothiophene, 2H- benzo[d][l,2,3]triazole benzofuran, indole, pyridine, quinoline, imidazole, benzimidazole, oxazole, tetrazole, and pyrazine.
  • “Pharmaceutically acceptable” refers to generally recognized for use in animals, and more particularly in humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an al
  • “Pharmaceutically acceptable excipient” refers to a broad range of ingredients that may be combined with a compound or salt of the present invention to prepare a pharmaceutical composition or formulation.
  • excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, preservatives, and the like.
  • Stepoisomer refers to an isomer that differs in the arrangement of the constituent atoms in space.
  • Stereoisomers that are mirror images of each other and optically active are termed “enantiomers,” and stereoisomers that are not mirror images of one another are termed “diastereomers.”
  • Subject includes mammals and humans.
  • “subject” are used interchangeably herein.
  • “Therapeutically effective amount” refers to the amount of a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom. As those skilled in the art will recognize this amount is typically not limited to a single dose, but may comprise multiple dosages over a significant period of time as required to bring about a therapeutic or prophylactic response in the subject. Thus, a “therapeutically effective amount” is not limited to the amount in a single capsule or tablet, but may include more than one capsule or tablet, which is the dose prescribed by a qualified physician or medical care provider.
  • the “therapeutically effective amount” can vary depending on the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be readily apparent to those skilled in the art or capable of determination by routine experimentation.
  • Treating" or “treatment” of any disease or disorder refers to arresting or ameliorating a disease, disorder, or at least one of the clinical symptoms of a disease or disorder, reducing the risk of acquiring a disease, disorder, or at least one of the clinical symptoms of a disease or disorder, reducing the development of a disease, disorder or at least one of the clinical symptoms of the disease or disorder, or reducing the risk of developing a disease or disorder or at least one of the clinical symptoms of a disease or disorder.
  • Treating” or “treatment” also refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both, or inhibiting at least one physical parameter which may not be discernible to the subject. Further, “treating” or “treatment” refers to delaying the onset of the disease or disorder or at least symptoms thereof in a subject which may be exposed to or predisposed to a disease or disorder even though that subject does not yet experience or display symptoms of the disease or disorder.
  • the invention provides a compound of Formula I:
  • R 1 and R 4 together with the C and N atoms of the triazole to which they are attached join to form a B ring, wherein the B ring is a 5 to 10 membered saturated or partially unsaturated ring that includes 0, 1, 2, or 3 heteroatoms independently selected from N, O, and S in addition to the N atom of the triazole that bears the R 4 substituent, wherein the B ring is substituted with 0, 1, 2, or 3 R B substituents; and further wherein the 5 to 10 membered B ring is fused to a C ring, wherein the C ring is selected from a phenyl ring, a 5 or 6 membered heteroaryl ring that includes 1, 2, or 3 heteroatoms independently selected from N, O, or S, a 5 to 7 membered heterocyclyl ring that includes 1, 2, or 3 heteroatoms independently selected from N, O, or S, or a C4 to Cg cycloalkyl ring, wherein the C ring is substituted with 0, 1, 2,
  • R B is independently selected from -F, -CI, -Br, -I, -Ci-Ce alkyl, -Ci-Ce haloalkyl, -Ci-Cg perhaloalkyl, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -CN, -OH, -0-(Ci-C 6 alkyl), -0-(Ci- C 6 haloalkyl), -0-(Ci-C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -0-(Ci-C 6 alkyl)-OH, -0-(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -0-(Ci-C 6 haloalkyl) -OH, -0-(Ci-C 6 haloalkyl)-0-(Ci-C 6 alkyl), - 0-(Ci-C 6 perhalo
  • R c is independently selected from -F, -CI, -Br, -I, -Ci-Ce alkyl, -Ci-Ce haloalkyl, - Ci-Ce perhaloalkyl, -(Ci-Ce alkyl)-0-(Ci-C 6 alkyl), -CN, -OH, -0-(Ci-C 6 alkyl), -0-(Ci- C 6 haloalkyl), -0-(Ci-C 6 perhaloalkyl), -C 2 -C 6 alkenyl, -0-(Ci-C 6 alkyl)-OH, -0-(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -0-(Ci-C 6 haloalkyl) -OH, -0-(Ci-C 6 haloalkyl)-0-(Ci-C 6 alkyl), - 0-(Ci-C 6 perhalo
  • R 2 is selected from -H, or C1-C4 alkyl
  • R 3 is selected from a group of formula -(CR 3b R 3c )-Q, a group of formula -(CR 3d R 3e )-(CR 3f R 3g )-Q, or a group of formula -(heterocyclyl)-Q, wherein the heterocyclyl of the -(heterocyclyl)-Q group has 5 to 7 ring members of which 1, 2, or 3 are heteroatoms independently selected from N, O, or S and is unsubstituted or is substituted with 1, 2, or 3 R 3h substituents;
  • R 3f and R 3g are independently selected from -H, -F, -CI, -CN, -Ci-C 6 alkyl, -Ci- C 6 haloalkyl, -Ci-C 6 perhaloalkyl, -OH, -(Ci-C 6 alkyl)-OH, -(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -0-(Ci-C 6 alkyl), -0-(Ci-C 6 haloalkyl), -0-(Ci-C 6 perhaloalkyl), -0-(C 2 -C 6 alkenyl), -0-(Ci-C 6 alkyl)-OH, -0-(Ci-C 6 alkyl)-0-(Ci-C 6 alkyl), -NH 2 , -NH(Ci-C 6 alkyl), or -N(Ci-C 6 alkyl) 2 ;
  • Q is a monocyclic or bicyclic Cs-Cio aryl group, a monocyclic or bicyclic heteroaryl group with 5 to 10 ring members containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, a C3-C8 cycloalkyl group, a 3 to 10 membered heterocyclyl group containing 1, 2, or 3 heteroatoms independently selected from N, O, or S, wherein the Ce-Cw aryl, the heteroaryl, the cycloalkyl, and the heterocyclyl Q groups are unsubstituted or are substituted with 1, 2, 3, or 4 R Q substituents; and further wherein the Q heterocyclyl group may additionally be substituted with 1 or 2 oxo substituents, and the Q heteroaryl group may include an N-oxide if the heteroaryl includes a N heteroatom; and
  • alkyl alkyl
  • alkyl alkyl
  • Formula I has the Formula IIA, IIB, IIC, IID, HE, or IIF
  • Formula I has the Formula IIA or is the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof.
  • Formula I has the Formula IIB or is the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof.
  • Formula I has the Formula IIC or is the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof.
  • Formula I has the Formula IID or is the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof.
  • Formula I has the Formula HE or is the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof.
  • Formula I has the Formula IIF or is the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof.
  • R 3d and R 3e are independently selected from -H or -Ci-Ce alkyl
  • R 3f and R 3g are independently selected from -H, -Ci-Ce alkyl or -0-(Ci-C6 alkyl).
  • R 3d and R 3e are independently selected from -H or -CH 3 ;
  • R 3f and R 3s are independently selected from -H, -CH 3 , -0-CH 3 , or -0-CH(CH 3 ) 2 .
  • a pharmaceutical composition comprising the compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, or the mixture thereof, and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising the compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising the compound of any one of embodiments 1-54 and at least one pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising the pharmaceutically acceptable salt of the compound of any one of embodiments 1-54 and at least one pharmaceutically acceptable excipient.
  • a therapeutic agent selected from an a-blocker, a ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.
  • ACE angiotensin converting enzyme
  • ARB angiotensin-receptor blocker
  • NEP neutral endopeptidase
  • a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).
  • ACE angiotensin converting enzyme
  • ARB angiotensin-receptor blocker
  • a method of treating a cardiovascular condition comprising: administering to a subject an effective amount of the compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof, or the mixture thereof, or the pharmaceutical composition of any one of embodiments 55-58.
  • a method of improving cardiac contractility in a subject suffering from a cardiovascular condition comprising: administering to the subject an effective amount of the compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof, or the mixture thereof, or the pharmaceutical composition of any one of embodiments 55-58, wherein cardiac contractility is improved in the subject after administration.
  • a method of increasing ejection fraction in a subject suffering from a cardiovascular condition comprising: administering to the subject an effective amount of the compound of any one of embodiments 1-54 or the
  • a method of treating a condition in a subject where it is desired to activate the APJ Receptor comprising: administering to the subject an effective amount of the compound of any one of embodiments 1-54 or the
  • the method includes administering at least one additional therapeutic agent to the subject, wherein the additional therapeutic agent is selected from an a-blocker, a ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.
  • the additional therapeutic agent is selected from an a-blocker, a ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.
  • ACE angiotensin converting enzyme
  • ARB angiotensin-receptor blocker
  • NEP neutral endopeptidase
  • 74 The method of any one of embodiments 61-72, wherein the method includes administering at least one additional therapeutic agent to the subject, wherein the additional therapeutic agent is selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).
  • ACE angiotensin converting enzyme
  • ARB angiotensin-receptor blocker
  • a therapeutic agent selected from an a-blocker, a ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.
  • ACE angiotensin converting enzyme
  • ARB angiotensin-receptor blocker
  • NEP neutral endopeptidase
  • embodiment 85 further comprising a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin- receptor blocker (ARB).
  • ACE angiotensin converting enzyme
  • ARB angiotensin- receptor blocker
  • a treatment regimen for a cardiovascular disease comprising: the compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof, or the mixture thereof.
  • a-blocker selected from an a-blocker, a ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.
  • ACE angiotensin converting enzyme
  • ARB angiotensin-receptor blocker
  • NEP neutral endopeptidase
  • ACE angiotensin converting enzyme
  • ARB angiotensin-receptor blocker
  • kits comprising: the compound of any one of embodiments 1-54 or the pharmaceutically acceptable salt thereof, or the mixture thereof.
  • kit of embodiment 100 wherein the kit further comprises a therapeutic agent selected from an a-blocker, a ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.
  • a therapeutic agent selected from an a-blocker, a ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.
  • ACE angiotensin converting enzyme
  • ARB angiotensin-receptor blocker
  • NEP neutral endopeptidase
  • kits of embodiment 100 wherein the kit further comprises a therapeutic agent selected from an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).
  • ACE angiotensin converting enzyme
  • ARB angiotensin-receptor blocker
  • the compound is a salt.
  • Such salts may be anhydrous or associated with water as a hydrate.
  • the compound may be in a neutral form as a base or an acid.
  • compositions that include the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments and at least one pharmaceutically acceptable excipient, carrier or diluent.
  • the compound or the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof according to any one of the embodiments is present in an amount effective for the treatment of a cardiovascular condition or other condition such as obesity or diabetes, for activating the APJ Receptor.
  • the pharmaceutical composition is formulated for oral delivery whereas in other
  • the pharmaceutical composition is formulated for intravenous delivery. In some embodiments, the pharmaceutical composition is formulated for oral administration once a day or QD, and in some such formulations is a tablet.
  • the subject is a mammal. In some such embodiments, the mammal is a rodent. In other such embodiments, the mammal is a canine. In still other embodiments, the subject is a primate and, in some such embodiments, is a human.
  • compositions or formulations for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with other nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid, or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate, or kaolin
  • an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy -propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally -occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy-ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin, or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally -occurring gums, for example gum acacia or gum tragacanth, naturally -occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include, for example, cocoa butter and polyethylene glycols.
  • compositions, ointments, jellies, solutions, or suspensions, etc., containing the compounds of the invention are employed.
  • topical application is also meant to include the use of mouthwashes and gargles.
  • the compounds of the invention can be administered to provide systemic distribution of the compound within the patient. Therefore, in some embodiments, the compounds of the invention are administered to produce a systemic effect in the body.
  • the compounds of the invention may be administered via oral, mucosal (including sublingual, buccal, rectal, nasal, or vaginal), parenteral (including subcutaneous, intramuscular, bolus injection, intra-arterial, or intravenous), transdermal, or topical administration.
  • the compounds of the invention are administered via mucosal (including sublingual, buccal, rectal, nasal, or vaginal), parenteral (including subcutaneous, intramuscular, bolus injection, intra-arterial, or intravenous), transdermal, or topical administration.
  • the compounds of the invention are administered via oral administration.
  • the compounds of the invention are not administered via oral
  • the compound of the invention may find use in treating a number of conditions.
  • the invention comprises methods or uses that include the use or administration of the compound, the
  • the cardiovascular condition includes, but is not limited to, coronary heart disease, stroke, heart failure, systolic heart failure, diastolic heart failure, diabetic heart failure, heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, cardiomyopathy, myocardial infarction, myocardial remodeling after cardiac surgery, valvular heart disease, hypertension including, essential hypertension, pulmonary hypertension, portal hypertension, systolic hypertension, aortic aneurysm such as abdominal aortic aneurysm, or atrial fibrillation including improving arrhythmia.
  • the cardiovascular condition is heart failure.
  • the heart failure is heart failure with reduced ejection fraction whereas in other embodiments it is heart failure with preserved ejection fraction.
  • the subject may have systolic heart failure or chronic diastolic heart failure and is thus useful in treating heart failure patients with systolic dysfunction and in treating heart failure patients with diastolic dysfunction.
  • the heart failure is heart failure with reduced ejection fraction whereas in other embodiments it is heart failure with preserved ejection fraction.
  • the subject may have systolic heart failure or chronic diastolic heart failure and is thus useful in treating heart failure patients with systolic dysfunction and in treating heart failure patients with diastolic dysfunction.
  • the heart failure is heart failure with reduced ejection fraction whereas in other embodiments it is heart failure with preserved ejection fraction.
  • the subject may have systolic heart failure or chronic diastolic heart failure and is thus useful in treating heart failure patients with systolic dysfunction and in treating heart failure patients
  • cardiovascular condition may be acute heart failure whereas in other embodiments, the cardiovascular condition is hypertension.
  • the compounds of the invention may be used to treat a number of diseases and disorders.
  • the invention provides a method of treating a disease or disorder selected from acute decompensated heart failure, chronic heart failure, pulmonary hypertension, atrial fibrillation, Brugada syndrome, ventricular tachycardia, atherosclerosis, hypertension, restenosis, ischemic cardiovascular diseases, cardiomyopathy, cardiac fibrosis, arrhythmia, water retention, diabetes, gestational diabetes, obesity, peripheral arterial disease, cerebrovascular accidents, transient ischemic attacks, traumatic brain injuries, amyotrophic lateral sclerosis, burn injuries, sunburn, edema, and preeclampsia in a subject.
  • a disease or disorder selected from acute decompensated heart failure, chronic heart failure, pulmonary hypertension, atrial fibrillation, Brugada syndrome, ventricular tachycardia, atherosclerosis, hypertension, restenosis, ischemic cardiovascular diseases, cardiomyopathy, cardiac fibrosis, arrhythmia,
  • Such methods include administering a compound of the invention, a pharmaceutically acceptable salt thereof, a tautomer thereof, a pharmaceutically acceptable salt of the tautomer, a stereoisomer of any of the foregoing, a mixture thereof, or a pharmaceutical composition that includes any of these to a subject in need thereof.
  • the invention provides a method of improving cardiac contractility in a subject suffering from a cardiovascular condition which includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject.
  • the improvement in cardiac contraction may lead to significant improvements in methods for treating heart failure patients.
  • the invention provides a method of improving cardiac relaxation in a subject suffering from a cardiovascular condition which includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject.
  • the improvement in cardiac relaxation may lead to significant improvements in methods for treating heart failure patients.
  • the invention provides a method of improving ventricular arterial coupling in a subject suffering from a cardiovascular condition which includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject.
  • the improvement in ventricular arterial coupling may lead to significant improvements in methods for treating heart failure patients.
  • the invention provides a method of increasing ejection fraction in a subject suffering from a cardiovascular condition which includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject.
  • the compounds of the invention may also find potential benefit in improving cardiac relaxation and thus find utility in treating certain heart failure patients.
  • the compounds of the invention may thus find utility in improving inotropic function in some embodiments and may also find utility in improving lusitropic function.
  • the invention provides a method of treating condition in a subject where it is desired to activate the APJ Receptor.
  • Such methods include administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject.
  • the condition is obesity or diabetes whereas in other embodiments, the condition is diabetic nephropathy or chronic kidney disease. In some such embodiments, the condition is type II diabetes.
  • the compounds of the invention may find utility in treating a number of other conditions.
  • the compounds of the invention may find utility in treating patients with conditions related to renal perfusion, hyperglycemia, aquaresis, and diuresis.
  • the invention provides a method of treating one of these subjects that includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject.
  • the compounds of the invention may further find utility in arginine vasopressin (A VP) regulation and in angiotensin receptor (AT1R) regulation.
  • a VP arginine vasopressin
  • AT1R angiotensin receptor
  • the compounds of the invention may find utility in treating a number of other conditions or producing desired outcomes or results.
  • the compounds of the invention may find utility in activating stem cells, more specifically cardiac stem cells, and even more specifically endogenous cardiac stem cells.
  • the compounds of the invention may find utility in activating heart stem cells in a subject such as in a human patient.
  • the compounds of the invention may yet further find utility in regrowing tissue and in assisting functional recovery after transplanting cells such as cells with bone marrow-derived mesenchymal stem cells.
  • the compounds of the invention may also find utility in increasing cardiac stem cell proliferation and may be used to do such in patients that have suffered a myocardial infarction.
  • the compounds of the invention may find utility in reducing infarct size, in promoting cardiac repair, and in activating stem cells and progenitors in post-myocardial infarction subjects.
  • the compounds of the invention may be used during surgery such as heart bypass surgery or heart transplant procedures as a therapeutic to reduce reperfusion injury.
  • the invention provides a method of treating one of these subjects or improving the condition in a subject that includes administration of the compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention to the subject.
  • Some methods of the invention comprise the administration of a compound of the invention and an additional therapeutic agent (i.e., a therapeutic agent other than a compound of the invention).
  • additional therapeutic agents include, but are not limited to, antibiotics, anti-emetic agents, antidepressants, antifungal agents, anti-inflammatory agents, antineoplastic agents, antiviral agents, cytotoxic agents, and other anticancer agents, immunomodulatory agents, alpha-interferons, ⁇ -interferons, alkylating agents, hormones, and cytokines.
  • the invention encompasses administration of an additional therapeutic agent that is used to treat subjects with chronic heart failure or hypertension.
  • some methods of the invention comprise the administration of a compound of the invention and an additional therapeutic agent (i.e., a therapeutic agent other than a compound of the invention).
  • the invention encompasses administration of an additional therapeutic agent that is used to treat subjects with chronic heart failure or hypertension.
  • the invention comprises methods or uses that include the use of a compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention and a therapeutic agent such as, but not limited to, an a-blocker, a ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, a neutral endopeptidase (NEP) inhibitor, a vasodilator, an aldosterone antagonist, a natriuretic, a saluretic, a centrally acting hypertensive, an aldosterone synthase inhibitor, or an endothelin receptor antagonist.
  • a therapeutic agent such as, but not limited to, an a-blocker, a ⁇ -block
  • the invention comprises methods or uses that include the use of a compound, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof of the invention and a therapeutic agent selected from an a-blocker, a ⁇ -blocker, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), a calcium channel blocker, a diuretic, an inhibitor of the funny current, a myosin activator, or a neutral endopeptidase (NEP) inhibitor.
  • ACE angiotensin converting enzyme
  • ARB angiotensin-receptor blocker
  • NEP neutral endopeptidase
  • the invention includes a method that includes administering a compound of the invention, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof and an additional therapeutic agent such as an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).
  • an additional therapeutic agent such as an angiotensin converting enzyme (ACE) inhibitor or an angiotensin-receptor blocker (ARB).
  • the additional therapeutic agent is thus an angiotensin converting enzyme (ACE) inhibitor whereas in others it is an angiotensin-receptor blocker (ARB).
  • ACE angiotensin converting enzyme
  • ARB angiotensin-receptor blocker
  • the invention includes a method that includes administering a compound of the invention, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof and an additional therapeutic agent such as a neutral endopeptidase (NEP) inhibitor.
  • the invention includes a method that includes administering a compound of the invention, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof and an additional therapeutic agent such as an inhibitor of the funny current.
  • the method of use may include two or more additional therapeutic agents.
  • the invention may include a compound of the invention, the pharmaceutically acceptable salt thereof, the tautomer thereof, the pharmaceutically acceptable salt of the tautomer, the stereoisomer of any of the foregoing, or the mixture thereof and additional therapeutic agents such as an ACE inhibitor and a NEP inhibitor.
  • Therapeutic agents such as a-blockers may be used in conjunction with the compounds of the invention.
  • ⁇ -blockers include, but are not limited to, doxazosin, prazosin, tamsulosin, and terazosin and their pharmaceutically acceptable salts.
  • Therapeutic agents such as ⁇ -blockers may be used in conjunction with the compounds of the invention.
  • ⁇ -blockers include, but are not limited to, acebutolol, acetutolol, atenolol, bisoprol, bupranolol, carteolol, carvedilol, celiprolol, esmolol, mepindolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, taliprolol, and their pharmaceutically acceptable salts.
  • Calcium channel blockers may also be used as therapeutic agents in conjunctions with the compounds of the present invention.
  • Examples of calcium channel blockers include, but are not limited to, dihydropyridines (DHPs) and non-DHPs.
  • DHPs include, but are not limited to, amlodipine, felodipine, isradipine, lacidipine, nicardipine, nifedipine, nigulpidine, nilutipine, nimodiphine, nisoldipine, nitrendipine, nivaldipine, ryosidine, and their pharmaceutically acceptable salts.
  • Non-DHPs include, but are not limited to, anipamil, diltiazem, fendiline, flunarizine, gallpamil, mibefradil, prenylamine, tiapamil, verapamil, and their pharmaceutically acceptable salts.
  • Diuretics may also be used in conjunction with the compounds of the present invention.
  • Examples include, but are not limited to, thiazide derivatives such as, but not limited to, amiloride, chlorothalidon, chlorothiazide, hydrochlorthiazide, and methylchlorothiazide and pharmaceutically acceptable salts thereof.
  • Centrally acting hypertensive agents may also be used in conjunction with the compounds of the present invention. Examples, include, but are not limited to, clonidine, guanabenz, guanfacine, methyldopa, and pharmaceutically acceptable salts thereof.
  • ACE inhibitors may be used in conjunction with the compounds of the present invention.
  • ACE inhibitors that may be used include, but are not limited to, alaceptril, benazepril, benazaprilat, captopril, ceronapril, cilazapril, delapril, enalapril, analaprilat, fosinopril, Lisinopril, moexipiril, moveltopril, perindopril, quinapril, quinaprilat, ramipril, ramiprilat, spriapril, temocapril, trendolapril, and zofenopril and their pharmaceutically acceptable salts.
  • examples of some dual ACE/NEP inhibitors include, but are not limited to omapatrilat, fasidotril, and fasidotrilat and their pharmaceutically acceptable salts.
  • ARBs may also be used as therapeutic agents in conjunction with the compounds of the present invention.
  • ARBs include, but are not limited to, candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, and valsartan and their pharmaceutically acceptable salts.
  • examples of some dual ARB/NEP inhibitors include, but are not limited to combinations of valsartan and sacubitril and their pharmaceutically acceptable salts.
  • NEP inhibitors may also be used as therapeutic agents in conjunction with the compounds of the present invention.
  • An example of a NEP inhibitor includes, but it not limited to, sacubitril and its pharmaceutically acceptable salts.
  • Aldosterone synthase inhibitors may also be used as therapeutic agents in combination with the compounds of the present invention.
  • aldosterone synthase inhibitors include, but are not limited to, anastrozole, fadrozole, and exemestane and their pharmaceutically acceptable salts.
  • Endothelin antagonists are other therapeutic agents that may be used in conjunction with the compounds of the present invention. Examples include, but are not limited to, bosentan, enrasentan, atrasentan, darusentan, macitentan, sitaxentan, and tezosentan, and their pharmaceutically acceptable salts.
  • Inhibitors of the funny current may also be used in conjunction with the compounds of the invention.
  • An example of an inhibitor of the funny current is ivabradine and its pharmaceutically acceptable salts.
  • Myosin activators may also be used in conjunction with the compounds of the invention.
  • Examples of myosin activators include cardiac myosin activators.
  • a therapeutic agent other than one of the present invention includes compounds such as known prodrugs that are converted into the therapeutic agent after administration.
  • a compound without antineoplastic activity, but that is converted into an antineoplastic agent in the body after administration may be administered along with a compound of the invention.
  • sacubitril is considered a NEP inhibitor for the purposes of this application even though it is a prodrug that is converted into sacubitrilat by de- ethylation via esterases.
  • the therapeutic agents can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition.
  • co-therapy in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace coadministration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent.
  • administration of compounds of the present invention may be in conjunction with additional therapies known to those skilled in the art in the prevention or treatment of cardiovascular conditions.
  • NMR spectra were recorded on a Bruker AV-400 (400 MHz) spectrometer or a Varian 400 MHz spectrometer at ambient temperature, or the NMR spectra were collected with a Bruker Avance III spectrometer operating at a proton frequency of 500.13 MHz using a 10 ⁇ .
  • Protasis CapNMR flow probe NMR samples were delivered to the flow probe using a Protasis One -Minute NMRTM Automation system comprised of a Discovery TowerTM Sample Manager and a Waters Liquid Handler made by CTC, Switzerland (Model 2777).
  • a wide variety of sulfonamide tails can be used to synthesize compounds of the invention such as those set forth in WO 2016/187308 and U.S. Pat. Appl. Pub. No. US 2016/0340336 which are hereby incorporated by reference in their entireties and for all purposes as if specifically set forth herein.
  • compounds of the present invention may be prepared using any of the R 3 and Q groups taught in WO 2016/187308 and U.S. Pat. Appl. Pub. No. US 2016/0340336 which are both incorporated herein by reference in their entireties and for all purposes.
  • Example 1.2 was synthesized following the procedure in Example 10.1 using 2- chloro-5-methoxypyrimidine (commercially available from Sigma Aldrich). LCMS ESI (pos.) m/z: 246.2 (M+H) + .
  • Example 1.2 (290 mg, 1.182 mmol) and cesium carbonate (501 mg, 1.54 mmol) in ACN (7882 ⁇ ,) was added Example 1.1 (215 mg, 1.241 mmol), and the reaction mixture was stirred at 23 °C for 15 h. The reaction mixture was then cooled to 0 °C. To the reaction mixture was added 2-bromobenzohydrazide (commercially available from Sigma- Aldrich, 267 mg, 1.24 mmol) and silver(I) nitrate (402 mg, 2.364 mmol) slowly. The reaction mixture was stirred at 23 °C for 1 h.
  • Example 1.3 To a solution of Example 1.3 (666 mg, 1.11 mmol) in IPA (7.4 mL) was added an aqueous solution of sodium hydroxide (1 N, 3.3 mL, 1.67 mmol). The reaction was stirred at 80 °C for 8 days. The reaction mixture was cooled to RT, diluted with a saturated solution of NH 4 C1 and extracted with DCM. The DCM solution was rinsed with water. The organic extract was concentrated in vacuo to give a light-yellow solid.
  • Example 1.4 To a stirred suspension of Example 1.4 (330 mg, 0.568 mmol) and 2-(trimethylsilyl)ethanol (1.4 mL, 1.14 mmol) in toluene (2 mL) in a 50-mL round-bottomed flask, was added (tributylphosphoranylidene)acetonitrile (1M solution in toluene, 1.1 mL, 1.135 mmol) dropwise at RT. The mixture was then stirred at 90 °C. LCMS analysis indicated a clean conversion after 20 min. The mixture was allowed to cool to RT.
  • Example 1.5 360 mg, 0.528 mmol, 93 % yield) as an orange solid.
  • LCMS-ESI (pos.) m/z: 681.1, 683.1 (M+H) + .
  • Example 1.6 (188 mg, 0.29 mmol), 2-(di-tert-butylphosphino)- 2',4',6'- triisopropyl-3,6-dimethoxy-l,l'-biphenyl (14.20 mg, 0.029 mmol) and cesium carbonate (191 mg, 0.59 mmol) in ACN (2.9 mL) was bubbled with argon gas for 2 min before tert-BuBrettPhos-Pd-G3, [(2-Di-/er/-butylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-lJ'-biphenyl)-2-(2'-amino-lJ'-biphenyl)]palladiurri(II) methane sulfonate (25.03 mg, 0.029 mmol) was added under a stream of argon.
  • the reaction mixture was stirred at 80 °C for 1 h.
  • the reaction mixture was allowed to cool to RT.
  • the reaction mixture was diluted with saturated NH 4 C1 and extracted with DCM.
  • the organic extract was concentrated in vacuo to give an orange solid.
  • the material obtained was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g) eluting with a gradient of 0% to 100% 1/3 EtOH/EtoAc in heptane to afford the title compound Example 1.7 (138 mg, 84 % yield) as a light yellow s + .
  • Example 1.7 (138 mg, 0.25 mmol) in THF (2.05 mL) under a stream of argon.
  • the solution was cooled to -78 °C and a solution of sodium bis(trimethylsilyl)amide (1 M solution in THF, 345 ⁇ ,, 0.345 mmol) was added.
  • the reaction mixture was stirred at -78 °C for 30 min before methyl iodide (30.8 ⁇ ,, 0.492 mmol) was added.
  • the reaction mixture was then stirred at -78 °C to 0 °C for 2 h.
  • the reaction mixture was then allowed to warm to RT and the stirring continued fori h.
  • Example 1.8 (118 mg, 0.205 mmol) and tris(dimethylamino)sulfonium difluorotrimethylsilicate (Sigma- Aldrich, 113 mg, 0.41 lmmol) in DMF (2053 ⁇ ,) under an argon stream.
  • the reaction mixture was stirred at 80 °C for 90 min.
  • the reaction mixture was diluted with water and extracted with EtOAc. The organic extract was concentrated in vacuo to give the initial material as an orange solid.
  • Example 22.0 Preparation of (1 S,2S)-N-((R)-5-((4- fluorophenoxy)methyl)-5,6-dihydrobenzo[f] [l,2,4]triazolo[4,3-d] [l,4]oxazepin-3-yl)- l-isopropoxy-l-(5-methylpyrimidin-2-yl)propane-2-sulfonamide and (1S,2S)-N-((S)-
  • Example 22.1 A solution of Example 22.1 (210 mg, 0.36 mmol), 4-fluorophenol (60.0 mg, 0.54 mmol) and triphenylphosphine (140 mg, 0.54 mmol) in THF (1.8 mL) was bubbled with argon gas for 2 min before diisopropyl azodicarboxylate (105 ⁇ ,, 0.535 mmol) was added in a dropwise stream at 0 °C. The reaction mixture was stirred at 0 to 23 °C for 18 h. The residual reaction mixture was diluted with water and extracted with DCM. The organic extract was concentrated in vacuo to give an orange solid.
  • Example 4.1 Preparation of iVyV-bis(4- methoxybenzyl)ethanesulfonamide.
  • Example 4.11 (1112 g, 99% yield) as a semi-solid. The material was used directly in the next step without further purification.
  • reaction mixture was then stirred at RT for 3 h.
  • 5-methylpyrimidine-2- carbonitrile (Example 4.13, 50 g, 420 mmol, 1.0 equiv) in THF (100 mL) at 0 °C and the mixture was stirred at RT for 2 h.
  • the reaction was then quenched with HC1 (1.5N, 500 mL) and water (2000 mL) and stirred for 10 min.
  • the mixture was extracted with EtOAc (2 x 1 L) and the combined organic layers were washed with brine (500 mL), dried over Na2S04, and filtered.
  • Example 4.15 (180 g, 352 mmol) in MeOH (1.8 L) were added zinc triflate (256 g, 704 mmol) and (S)-RuCl[(p-cymene(BINAP)]Cl (6.54 g,7.04 mmol). The mixture was heated at 60 °C under H 2 pressure (60 psi) for 16 h. The reaction mixture was concentrated in vacuo to obtain the initial product which was further purified by column chromatography using silica gel (60-120 mesh) and 0-50% EtOAc in DCM as eluent to obtain Example 4.16 (140 g, 77 %, 92% ee) as an off white solid.
  • Example 4.1 72 g, 97 % yield, 90% ee
  • Example 4.1 72 g, 90% ee
  • IPA 500 mL
  • Example 4.1 was suspended in IPA (500 mL) and heated to 70 °C until the mixture become homogeneous. Once the solution became homogeneous, the mixture was cooled to RT overnight.
  • the white solid thus obtained was filtered and dried under vacuum to obtain Example 4.1 (30 g, >99%ee).
  • the mother liquor was concentrated and the solid obtained was recrystallized again following the same procedure.
  • Example 10.12 To a solution of pyrimidine-2 -thiol (14.8 g, 132 mmol) in DCM (440 mL) was added sulfuryl chloride (10.73 mL, 132 mmol). The reaction was stirred at 0 °C for 1 h and a further 1 h at RT. To the cloudy reaction mixture was added Example 10.11 (20 g, 132 mmol) dropwise, and the mixture was stirred for 2 h. The reaction mixture was then concentrated in vacuo. Aqueous sodium bicarbonate solution was added to the mixture to neutralize the reaction mixture. The reaction was extracted with EtOAc and concentrated in vacuo. The residue was purified on silica gel with 0-25% EtOAc in hexanes to give Example 10.12 (30 g, 76% yield).
  • Example 10.13 (33.2 g, 100 mmol, 100% yield).
  • Example 10.14 To a solution of Example 10.13 (33 g, 100 mmol) in MeOH (249 mL) was added potassium carbonate (27.6 g, 200 mmol). The reaction was stirred at RT for 16 h. The reaction was concentrated in vacuo to give Example 10.14 (21.57 g, 100% yield) and was used without further purification.
  • Example 10.15 To a solution of Example 10.14 (21.57 g, 85 mmol) in water (424 mL, 85 mmol) was added potassium acetate (5.30 mL, 85 mmol) followed by amidoperoxymonosulfuric acid (19.18 g, 170 mmol). The reaction was stirred at RT for 24 h. The reaction was extracted with EtOAc and concentrated in vacuo. The product thus obtained was purified on silica gel eluting with 0-50% EtOAc in hexanes to give Example 10.15 (12 g, 61% yield).
  • Example 10.15 (40.00 g, 0.176 mol), zinc trifluoromethane sulfonate (12.79 g, 0.0352 mol, commercially available from Aldrich), bis(l,5-cyclooctadiene)rhodium(I) tetrafluoroborate (1.43 g, 0.00352 mol, commercially available from Strem Chemicals, Inc.), (S)-l-[(R)-2-(Di-l- naphtylphosphino)ferrocenyl]-ethyl-di-tert.-butylphosphine (2.60 g, 0.00405 mol, commercially available from Solvias) and MeOH (520 mL).
  • the mixture was purged with nitrogen and then with hydrogen, and the reaction was stirred under 3-4 bars of hydrogen for 20 h.
  • the reaction was monitored by HPLC and showed a complete conversion.
  • the reactor was purged with nitrogen and the resulting suspension was concentrated at 35 °C under vacuum to give the initial material as an orange solid.
  • the initial material was mixed with EtOH (742 mL) and the resulting suspension was stirred at 20-25 °C for 40 minutes.
  • the solid was filtered, washed with EtOH (2 x 97 mL) and dried at 40 °C under vacuum to give Example 10.1 as a white powder (85% yield, 99%ee).
  • Example 24.1 Preparation of (lR,2S)-l-methoxy-l-(5- methylpyrimidin-2-yl)propane-2-sulfonamide.
  • Example 24.11 (12.96 g, 97 mmol, 100% yield) as a yellow/orange oily solid.
  • Example 24.11 (5.75 g, 42.9 mmol) and 4- methylmorpholine-4-oxide (7.53 g, 64.3 mmol) in acetone (60 mL) and water (6 mL) was added osmium tetroxide (4 wt.%, in water, 0.681 mL, 0.111 mmol).
  • osmium tetroxide (4 wt.%, in water, 0.681 mL, 0.111 mmol).
  • the reaction was passed through a Varian Chem-Elut cartridge to remove water and was then concentrated in vacuo. Water was still present.
  • a batch of AD-mix-beta was prepared from: K 2 Os0 2 (OH)4 (26 mg, 0.07 mmol), K 3 Fe(CN) 6 (16.4 g, 49.9 mmol), K 2 C0 3 (6.89 g, 49.9 mmol), and (DHQD) 2 PHAL (125 mg, 0.16 mmol).
  • the reaction was quenched with a saturated aqueous sodium sulfite solution (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with 2 N NaOH (10 mL), dried (MgSC ) and concentrated in vacuo. The aqueous layer was extracted with DCM (2 x 50 mL), EtOAc (2 x 50 mL) and 10% iPrOH in CHC1 3 (2 x 50 mL).
  • Example 24.13 To a solution of Example 24.12 (1.46 g, 8.68 mmol) in DCM (25 mL) (cooled with a RT water bath) was added 1,1,1-trimethoxy ethane (2.50 mL, 2.29 mmol).
  • Tris(((trifluoromethyl)sulfonyl)oxy)ytterbium (83 mg, 0.133 mmol) was then added. The suspension was heated in a 35 °C heating block for 17 h and showed 100% conversion to the desired product. The reaction was then cooled to RT, loaded on a plug of silica, and purified by flash chromatography (12 g Si0 2 , 5-100% 3: 1 EtOAc:EtOH/heptanes) to afford Example 24.14 (428 mg, 1.35 mmol, 100% yield) as a clear, colorless oil.
  • Example 24.15 2-(((lR,2S)-l-Methoxy-l-(5-methylpyrimidin-2-yl)propan-2- yl)thio)benzo[d]thiazole, Example 24.15.
  • a 50 mL flask equipped with a magnetic stirrer was charged with Example 24.14 (350 mg, 1.103 mmol) in 2- methyltetrahydrofuran (1.1 mL).
  • the reaction mixture was cooled to -78 °C and potassium bis(trimethylsilyl)amide (1M solution in THF, 1.32 ⁇ , 1.32 mmol) was added dropwise (total addition time: 2 min. and the solution turned yellow).
  • Example 24.16 2-(((lR,2S)-l-Methoxy-l-(5-methylpyrimidin-2-yl)propan-2- yl)sulfonyl)benzo[d]thiazole, Example 24.16.
  • a solution of Example 24.15 (313 mg, 0.94 mmol) in DCM (2.8 mL) at 0 °C was treated with 3-chloroperoxybenzoic acid (77% max., 476 mg, 2.13 mmol). The reaction was stirred at 0 °C for 1 h before the ice bath was removed. The mixture was allowed to warm to RT and stirred for an additional 40 h.
  • Example 24.16 (285 mg, 0.78 mmol, 83% yield, 77% purity) as a white foam.
  • LCMS-ESI (pos.) m/z: 364.0 (M+H).
  • Example 24.1 (114 mg, 0.465 mmol, 63.0% yield) as a white solid, (contained -15% other diastereomer).
  • Example 29.1. Preparation of 2-(5-methylpyrimidin- 2- yl)ethanesulfonamide.
  • Example 29.11 (100 g) as a yellow oil which was utilized in the next step without further purification.
  • TLC solvent system 20% EtOAc in hexanes, Product's Rf: 0.5.
  • Example 29.12 A solution of Example 29.11 (46.7 g, 389.0 mmol) in saturated aqueous sodium sulfite solution (200 mL) was stirred at RT for 12 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase flash
  • Example 29.12 (40.0 g, 51% yield) as a white solid.
  • LCMS-ESI (pos.) m/z: 203.1 (M+H) + .
  • Example 29.1 (10.5 g, 35% yield) as an off-white solid.
  • LCMS-ESI (pos.) m/z: 202.1 (M+H) + .
  • Example 29.0 Preparation of N-((5R)-5-(methoxymethyl)-5,6- dihydropyrido[3,2-f][l,2,4]triazolo[4,3-d] [l,4]oxazepin-3-yl)-2-(5-methyl-2- pyrimidinyl)ethanesulfonamide and N-((5S)-5-(methoxymethyl)-5,6- dihydropyrido[3,2-f][l,2,4]triazolo[4,3-d] [l,4]oxazepin-3-yl)-2-(5-methyl-2- pyrimidinyl)ethanesulfonamide.
  • Example 29.2 was synthesized following the procedure described in Example 1.0 using Example 1.1, Example 29.1 and 2-bromonicotinohydrazide (commercially available from SynChem Inc. Elk Grove Village, IL). LCMS-ESI (pos.) m/z: 556.0, 558.0 (M+H) + .
  • Example 29.2 (568 mg, 1.0 mmol) and KOH water solution (1.0 M, 1.0 mL) in water (5 mL).
  • the reaction mixture was stirred and heated in an Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 150 °C for 60 min.
  • the reaction mixture was then cooled to RT and treated with 2N HC1 (2 eq.) with stirring.
  • the resulting diol intermediate was concentrated and dried in vacuo.
  • the resulting dry mixture was then treated with CS2CO3 (3 eq.) in DMF (5 mL) at RT with stirring.
  • the reaction mixture was stirred at 80 °C for 2 h.
  • the mixture was allowed to cool to RT and filtered.
  • the solution was concentrated in vacuo and the residue was purified by reverse phase flash
  • Example 29.3 To a stirred suspension of Example 29.3 (350 mg, 0.838 mmol) and 2-(trimethylsilyl)ethanol (844 ⁇ ,, 6.71 mmol) in toluene (4192 ⁇ ,) was added (tributylphosphoranylidene)acetonitrile (1M solution in toluene, 1677 ⁇ ,, 1.68 mmol) dropwise at RT. The mixture was stirred at 90 °C for 40 min. The reaction mixture was then allowed to cool to RT.
  • Example 29.4 (180 mg, 0.348 mmol, 41.5 % yield) as an o + .
  • Example 29.0 was synthesized following the procedures described in Example 1.0 using Example 29.4.
  • Example 57.12. A solution of Example 4.12 (0.771 g, 2.208 mmol) was dissolved in THF (3.68 mL) and cooled to -78 °C using dry ice acetone bath (internal reaction temperatm ⁇ ath temperature not monitored).
  • Example 57.11 0.2 g, 1.104 mmol
  • THF 0.5 mL
  • the reaction was stirred at RT for -20 mins after which LCMS indicated complete consumption of Example 57.11 and conversion to product.
  • the reaction was quenched by addition to a separation funnel that contained 1M HC1 ( ⁇ 15 mL).
  • Example 48.0 Preparation of (P) (lS,2S)-N-((Z)-ll-fluoro-4,5- dihydrobenzo[g] [l,2,4]triazolo[4,3-a]azocin-l-yl)-l-isopropoxy-l-(5- methylpyrimidin-2-yl)propane-2-sulfonamide or (M) (lS,2S)-N-((Z)-ll-fluoro-4,5- dihydrobenzo[g] [l,2,4]triazolo[4,3-a]azocin-l-yl)-l-isopropoxy-l-(5- methylpyrimidin-2-yl)propane-2-sulfonamide.
  • Example 48.1 (Z)-N'-(2-Fluoro-6-vinylphenyl)-N-(((lS,2S)-l-isopropoxy-l-(5- methylpyrimidin-2-yl)propan-2-yl)sulfonyl)hydrazinecarboximidamide, Example 48.1.
  • Example 4.1 (0.80 g, 2.93 mmol) in ACN (15.0 mL) was added Example 48.11 (0.525 g, 2.93 mmol) and cesium carbonate (1.9 g, 5.85 mmol). The mixture stirred at RT for 5 h after which LCMS indicated complete consumption of starting material.
  • Example 48.1 (0.3 g, 0.67 mmol) in one portion, and the reaction was allowed to stir at RT. After 1 h, LCMS indicated complete consumption of starting materials. The reaction was concentrated in vacuo, and the mixture was loaded directly on to silica gel and purified (30-100% EtOAc:EtOH 3: 1 in heptane) to to afford Example 48.2 as a white solid (0.347 g, 0.65 mmol, 98 % yield). LCMS-ESI (pos.) m/z: +.
  • Example 48.2 To a solution of Example 48.2 (0.355 g, 0.597 mmol) in water (4.0 mL) was added potassium hydroxide (6N, 0.12 mL, 0.716 mmol). The resulting mixture was then heated to 100 °C. After 3 h, LCMS suggested loss of the of the starting material. The mixture was then neutralized to pH 7 using 1M HC1, diluted with water, and extracted with DCM. The combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated in vacuo.
  • potassium hydroxide 6N, 0.12 mL, 0.716 mmol
  • Example 48.3 (0.268 g, 0.52 mmol, 87 % yield) as mixture of atropis (pos.) m/z: 515.2 (M+H) + .
  • Example 48.3 (0.100 g, 0.194 mmol) in DCM (10.0 mL) under nitrogen atmosphere was added Grubb's 2nd generation catalyst (49.5 mg, 0.058 mmol). The reaction mixture was allowed to warm to 40 °C. After 16 h, LCMS suggested complete conversion of starting material. The reaction mixture was concentrated in vacuo.
  • Example 49.0 Preparation of (P)(lS,2S)-N-((Z)-ll-fluoro-4,5- dihydrobenzo[g][l,2,4]triazolo[4,3-a]azocin-l-yl)-l-isopropoxy-l-(5- methylpyrimidin-2-yl)propane-2-sulfonamide or (M)(lS,2S)-N-((Z)-ll-fluoro-4,5- dihydrobenzo[g][l,2,4]triazolo[4,3-a]azocin-l-yl)-l-isopropoxy-l-(5- methylpyrimidin-2-yl)propane-2-sulfonamide.
  • Example 146.0 Preparation of (R)-tert-butyl(2-isothiocyanato-2- phenylethoxy) dimethylsilane.

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Abstract

L'invention concerne des composés de formule I, des sels pharmaceutiquement acceptables de ceux-ci, des tautomères correspondants, des sels pharmaceutiquement acceptables desdits tautomères, ou des mélanges de ceux-ci, qui sont des agonistes du récepteur APJ et sont utiles dans le traitement d'affections cardiovasculaires et autres affections. Les composés de formule (I) ont la structure suivante : les définitions des variables étant fournies dans la description.
PCT/US2018/057466 2017-11-03 2018-10-25 Agonistes de triazole fusionnés du récepteur apj WO2019089335A1 (fr)

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